Estimates by the World Health Organization of the global prevalence of the top two articular joint diseases in people put the incidence of osteoarthritis (OA) in adults over 60 years of age at 9.6% of men and 18.0% of women (approximately 84 million people combined) and the incidence of rheumatoid arthritis (RA) in adults 25 years and older at 1% (approximately 42 million people). These rates of incidence are expected to increase nearly exponentially as the global population ages.
Both OA & RA share the same basic disease pathology in that the articular joints become inflamed, which leads to destruction of the cartilage that normally would cushion the joint. The inflammation and subsequent cartilage loss leads to joint stiffness and pain, at which point people begin looking for pharmacologic interventions to treat these symptoms. At this stage, the patients have likely had joint inflammation for many years, with cartilage destruction occurring asymptomatically the entire time. This makes the condition that much more difficult to treat. The lack of drugs that can halt the progression of arthritis (i.e be disease modifying) combined with the fact that it is diagnosed when it is more severe, results in OA & RA being a substantial burden for global healthcare systems. Because so many people acquire these debilitating diseases, there is an obvious current need for joint therapeutics and the future need will be substantially greater.
There are currently no approved disease modifying osteoarthritis drugs (DMOADs) and only a handful of disease modifying anti-rheumatic drugs (DMARDs) are approved, such as antibodies—with the latter having severe side effects, some of which can even be fatal. The ability to evaluate new joint therapeutics is paramount to the approval of new molecular entities or for new indications for existing drugs.
Various indicators of disease status (biomarkers) have been evaluated to better understand arthritis progression and/or prognosis and to better guide the development of therapeutic interventions. Researchers have looked at immune cell patterns in the joints, serological parameters (e.g. cholesterol & triglycerides) and markers of oxidative stress (e.g malondialdehyde & C-reactive protein (CRP), synovial fluid cytokine levels (e.g. TNF-α, IL-1β, IL-6, etc.), as well as cartilage components in synovial fluid (e.g. chondroitin sulfate, glycosaminoglycans, hyaluronic acid, etc.). Many of these biomarkers suffer from a number of drawbacks, from lack of specificity (e.g. cholesterol) to difficulty in obtaining samples (e.g. synovial fluid). Because of the plethora of biomarkers from which to choose to evaluate arthritis, the Osteoarthritis Biomarkers Network funded by the National Institutes of Health/National Institute of Arthritis, Musculoskeletal, and Skin Disease (NIH/NIAMS) proposed a classification scheme for biomarkers to provide a common format for communication of research in this area. This scheme is termed BIPED which is an acronym for Burden of disease, Investigative, Prognostic, Efficacy of intervention, and Diagnostic. These characteristics help to rank biomarkers as to their clinical utility in diagnosing and treating arthritis. Based upon these criteria, indicators of cartilage metabolism (i.e. synthesis and degradation) have moved to the top of the list of biomarker candidates likely to be most useful.
Cartilage is primarily composed of extracellular matrix (ECM), a composite network of proteins such as type-II collagen interacting with negatively charged polysaccharides such as hyaluronic acid and chondroitin sulfate, all of which are synthesized and secreted by the cells of cartilage known as chondrocytes. During normal cartilage turnover (metabolism) in healthy articular joints, ECM production balances ECM breakdown, thereby ensuring the continuous renewal of this critical joint-cushioning tissue. However under pathological (disease) conditions, ECM synthesis cannot keep pace with degradation and a loss of the structural integrity of the articular cartilage results. Products of this degradation imbalance can be found in both blood and urine of arthritic patients.
A number of these biomarkers of cartilage turnover (i.e. degradation & synthesis) have been investigated for their diagnostic and prognostic properties. Two of the most widely studied cartilage degradation biomarkers are c-terminal cross-linked telopeptide of type-II collagen (CTX-II) and cartilage oligomeric matrix protein (COMP). Two of the most widely studied cartilage synthesis biomarkers are procollagen type-IIA N-terminal propeptide (PIIANP) and carboxypeptide of procollagen type-II (CPII). Of all of the cartilage turnover biomarkers, urinary CTX-II has shown the most diagnostic and prognostic potential according to the BIPED system.
CTX-II has been associated with both the incidence and progression of osteoarthritis (OA) in multiple clinical trials and is predictive of the progression of OA both radiographically, including two 5+ year longitudinal studies, and by magnetic resonance imaging. Urinary CTX-II levels are known to be substantially elevated in the subset of the population with articular joint disease (i.e. OA & RA), but levels are also known to be elevated in a variety of healthy subsets of the population, as well.
For example, urinary CTX-II levels in growing children are about 50-fold higher than that of adults. Urinary CTX-II levels have been shown to be elevated due to high-impact, strenuous exercise in healthy college-aged endurance athletes such as cross-country runners by about 85% over age- and weight-matched controls, but were not significantly elevated in lower-impact endurance athletes like swimmers and rowers. Urinary CTX-II has also been shown to be about 2-fold higher in post-menopausal women versus age-matched pre-menopausal women and moderately elevated (˜25%) in overweight people (BMI ≥25 kg/m2) versus normal-weight controls (BMI <25 kg/m2).